Endothelin-1 (ET-1) is known to have potent contractile and proliferative effects on vascular smooth muscle cells and is known to induce myocardial cell hypertrophy. We studied the pathophysiological role of endogenous ET-1 in rats with monocrotaline-induced pulmonary hypertension. Four-week-old rats were given a single subcutaneous injection of 60 mg/kg monocrotaline (MCT rats) or saline (control rats) and were killed after 6, 10, 14, 18, and 25 days. In the MCT rats, right ventricular systolic pressure progressively increased and right ventricular hypertrophy developed in a parallel fashion. The venous plasma ET-1 concentration also progressively increased, and this increase preceded the development of pulmonary hypertension. The isolated pulmonary artery exhibited a significantly weaker response to ET-1 in the MCT rats on day 25 but not on days 6 and 14. In the MCT rats, the expression of prepro ET-1 mRNA as measured by Northern blot analysis significantly increased in the heart on days 18 and 25, whereas it gradually decreased in the lungs. The peptide level of ET-1 in the lungs also significantly decreased in the pulmonary hypertensive stage. The expression of prepro ET-1 mRNA had increased by day 6 only in the kidneys. disease, valvular heart disease, and left ventricular failure) and pulmonary diseases (eg, emphysema, lung fibrosis, and obstructive airway disease) are often accompanied by pulmonary hypertension, and the severity of pulmonary hypertension is one determinant of the prognosis of such patients.' Although some researchers believe that pulmonary vasoconstriction plays a role in the pathogenesis of pulmonary hypertension,"2 the mechanism for the progression of pulmonary hypertension is still poorly understood. Received October 26, 1992; accepted July 13, 1993. Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor peptide, was recently identified.3 This peptide induces proliferation of vascular smooth muscle cells.4 ET-1 has several properties suggestive of a potential pathophysiological role in pulmonary hypertension. First, ET-1 contracts isolated pulmonary vessels5 and increases pulmonary vascular resistance.6'7 Second, ET-1 has a mitogenic effect on vascular smooth muscle cells4'8'9 and fibroblasts,'0"' consistent with a role in vascular remodeling, a prominent finding in pulmonary hypertensive stages. ET-1 has also been reported to be produced by nonvascular tissues such as the heart, kidneys, and central nervous system.'2"3 It has been demonstrated that prepro ET-1 mRNA is expressed in cultured rat cardiomyocytes'4 and that ET-1-like immunoreactivity exists in the renal cortex and medulla of rats.15 In the heart, ET-1 induces myocardial cell hypertrophy'6 and has positive inotropic'7 and chronotropic'8 effects.A single subcutaneous injection of monocrotaline (MCT), a pyrrolizidine alkaloid, causes pulmonary hyby guest on

Central auditory relay synapses in mature animals follow high-frequency inputs for computation of sound localization. In immature mice, however, transmission at the calyx of Held synapse in auditory brainstem was inaccurate for high-frequency inputs because the summed slow synaptic potential components caused aberrant firings or blocked action potentials. As the mice matured, synaptic potentials became shorter, with smaller and faster NMDA receptor components, thereby establishing the precise one-to-one transmission for high-frequency inputs. Developmental acquisition of this high-fidelity transmission could be mimicked experimentally in immature mice by blocking NMDA receptors with d(-)2-amino-5-phosphonovaleric acid (d-APV). Furthermore, bilateral cochlear ablations at postnatal day 7 (P7) attenuated the developmental decrease of NMDA receptor expression and prevented the acquisition of high-fidelity transmission. We suggest that auditory activity, which begins at P10-P12 in mice, downregulates the expression of postsynaptic NMDA receptors, thereby contributing to the establishment of high-fidelity synaptic transmission.

GABA(A) receptor alpha1 and alpha2 subunits are expressed differentially with ontogenic period in the brain, but their functional roles are not known. We have recorded GABA(A) receptor-mediated IPSCs from laterodorsal (LD) thalamic relay neurons in slices of rat brain at various postnatal ages and found that decay times of evoked IPSCs and spontaneous miniature IPSCs undergo progressive shortening during the first postnatal month. With a similar time course, expression of transcripts and proteins of GABA(A) receptor alpha2 subunit in LD thalamic region declined, being replaced by those of alpha1 subunit. To further address the causal relationship between alpha subunits and IPSC decay time kinetics, we have overexpressed GABA(A) receptor alpha1 subunit together with green fluorescent protein in LD thalamic neurons in organotypic culture using recombinant Sindbis virus vectors. Miniature IPSCs recorded from the LD thalamic neurons overexpressed with alpha1 subunit had significantly faster decay time compared with control expressed with beta-galactosidase. We conclude that the alpha2-to-alpha1 subunit switch underlies the developmental speeding in the decay time of GABAergic IPSCs.

New neurons are added to the adult brain throughout life, but only half ultimately integrate into existing circuits. Sensory experience is an important regulator of the selection of new neurons but it remains unknown whether experience provides specific patterns of synaptic input, or simply a minimum level of overall membrane depolarization critical for integration. To investigate this issue, we genetically modified intrinsic electrical properties of adult-generated neurons in the mammalian olfactory bulb. First, we observed that suppressing levels of cell-intrinsic neuronal activity via expression of ESKir2.1 potassium channels decreases, whereas enhancing activity via expression of NaChBac sodium channels increases survival of new neurons. Neither of these modulations affects synaptic formation. Furthermore, even when neurons are induced to fire dramatically altered patterns of action potentials, increased levels of cell-intrinsic activity completely blocks cell death triggered by NMDA receptor deletion. These findings demonstrate that overall levels of cell-intrinsic activity govern survival of new neurons and precise firing patterns are not essential for neuronal integration into existing brain circuits.

The growth factor neuregulin 1 (NRG1) has been proposed to contribute to the formation and maturation of neuromuscular and interneuronal synapses by upregulating the expression of specific neurotransmitter receptor subunits. In the present report, we show that, in the hippocampus, NRG1 is expressed in a pattern suggesting that it regulates synapse development in the CA1 region. However, in contrast to what has been shown in other synapses, NRG1 reduces the expression of gamma-aminobutyric acid (GABA)A receptors alpha subunits in hippocampal slices, and the mean amplitude of GABAergic miniature inhibitory postsynaptic currents (IPSCs) in hippocampal CA1 pyramidal neurons, without affecting IPSC kinetics or frequency. These effects of NRG1 occur without concomitant changes in glutamate receptors and other synaptic proteins. We propose that the role of NRG1 in the formation and maturation in the hippocampal inhibitory synapse is downregulation, rather than upregulation, of receptor subunit expression. These results suggest that NRG1 may contribute to the reduction in GABAergic synaptic activity in hippocampal CA1 pyramidal neurons that normally occurs during early postnatal development, and that alterations in NRG1 signaling in the hippocampus may contribute to schizophrenia and epilepsy.